Discovery of a Novel ASM Direct Inhibitor with a 1,5-Diphenyl-pyrazole Scaffold and Its Antidepressant Mechanism of Action

Multiple studies have confirmed that acid sphingomyelinase
(ASM)
activity is associated with depression. The discovery of direct inhibitors
against ASM is of great significance for exploring antidepressants
and their mechanisms of action. Herein, a series of novel phenylpyrazole
analogues were rationally designed and synthesized. Among them, compound 46 exhibited potent inhibitory activity (IC50 =
0.87 μM) and good drug-like properties. In vivo studies demonstrated that compound 46 was involved
in multiple antidepressant mechanisms of action, which were associated
with a decline of ceramide, including increasing the Bcl-2/Bax ratio
and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating
oxidative stress, reducing the levels of proinflammatory cytokines
such as TNF-α, IL-1β, and IL-6, and elevating 5-HT levels
in the brains of mice, respectively. These meaningful results reveal
for the first time that direct inhibitors exhibit remarkable antidepressant
effects in the CUMS-induced mouse model through multiple mechanisms
of antidepressant action.

多项研究已证实，酸性鞘磷脂酶（acid sphingomyelinase, ASM）的活性与抑郁症存在显著关联。针对ASM的直接抑制剂的研发，对于探索抗抑郁药物及其作用机制具有重要价值。本研究中，研究人员通过合理设计与合成，得到了一系列新型苯基吡唑类类似物。其中，化合物46展现出强效的抑制活性（IC50 = 0.87 μM）及良好的成药性。体内实验表明，化合物46可通过多条通路发挥抗抑郁作用，其机制与神经酰胺水平降低密切相关，具体包括：上调Bcl-2/Bax比值与脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）的表达、下调半胱天冬氨酸蛋白酶-3（caspase-3）与半胱天冬氨酸蛋白酶-9（caspase-9）的活性、改善氧化应激状态、降低肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）及白细胞介素-6（IL-6）等促炎细胞因子的水平，以及提升小鼠脑内5-羟色胺（5-HT）的含量。本研究首次证实，针对ASM的直接抑制剂可通过多重抗抑郁作用机制，在慢性不可预见性温和应激（CUMS）诱导的小鼠抑郁模型中展现出显著的抗抑郁效果。